2- Androgens, estrogens, and sex differences in mitochondria.
We utilize a wide range of cellular and molecular approaches to investigate the hormonal regulation of signaling cascades that affect mitochondrial function and integrity. It is crucial to evaluate this response in both sexes, as the expression and level of mitochondrial proteins differ between males and females. To achieve this, we perform proteome and transcriptome profiling of male and female astrocytes, as well as whole-brain homogenates, in order to gain a deeper understanding of how sex and hormone crosstalk can influence the response of mitochondria to neurodegeneration.
Tibolone and testosterone preserve cell morphology and mitochondrial content, respectively, in astrocytic cells under glucose deprivation.
One of the major milestones of our group was the discovery that tibolone, a synthetic steroid drug used by women to alleviate symptoms associated with menopause, has the ability to upregulate neuroglobin. Our group has previously reported that tibolone preserves mitochondrial membrane potential, reduces oxidative stress, and improves cell survival following metabolic dysfunction in glial cells. In fact, our previous studies have shown that tibolone has anti-inflammatory, antioxidant, and anti-apoptotic properties, making it a promising candidate for repurposing in neurometabolic diseases, including neurodegenerative diseases.
Tibolone exerts neuroprotective actions mediated by estrogen receptors (Del Río et al., 2020).
Neuroglobin is currently a major focus of our laboratory, given its significant therapeutic potential for protecting both neurons and astrocytes from traumatic brain damage. We employ various pharmacological approaches and therapies in cultured astrocytes, neurons, and microglia to induce neuroglobin for mitochondrial protection. Our primary objective now is to investigate the molecular mechanisms of neuroglobin signaling in both male and female cells.
3D structure of human neuroglobin.
Employing network pharmacology to investigate protein-protein interaction networks enables us to explore druggable cellular targets implicated in neurodegenerative diseases, as well as identify hubs that may serve as drivers of these pathologies.
Interleukin-6 (IL6) as a hub regulated by tibolone and involved in traumatic brain injury pathology (McGovern and Barreto, 2021).